Trastuzumab (
Herceptin) is a humanized antibody directed against the extracellular domain of the
tyrosine kinase orphan receptor Her-2/neu (erbB-2) that has shown therapeutic efficacy against Her-2/neu-overexpressing
breast tumors. However, less than 35% of patients with Her-2/neu-overexpressing metastatic
breast cancer respond to
trastuzumab as a single agent, whereas the remaining cases do not demonstrate
tumor regression. Furthermore, the majority of patients who achieve an initial response generally acquire resistance within one year. Therefore, the identification of the potential mechanisms of resistance to
trastuzumab can be very helpful for the development of new compounds, which might overcome that resistance and/or have additive/synergistic antitumor effect when given in association with
trastuzumab. Recent studies in
breast cancer cells have revealed a bi-directional connection between Her-2/neu and
fatty acid synthase (FAS), a major lipogenic
enzyme catalyzing the synthesis of long-chain
saturated fatty acids from the 2-carbon donors
malonyl-CoA and
acetyl-CoA. Her-2/neu overexpression stimulates the FAS promoter and ultimately mediates increased endogenous fatty synthesis, and this Her-2/neu-mediated induction of
breast cancer-associated FAS is inhibitable by
trastuzumab. On the other hand, chemical FAS inhibitors as well as RNA interference-mediated silencing of FAS gene repress Her-2/neu gene expression at the transcriptional level. Moreover, specific FAS blockade synergistically sensitizes
breast cancer cells carrying Her-2/neu-oncogene amplification and/or overexpression to
trastuzumab-induced cell growth inhibition and apoptotic cell death. Strikingly, FAS inhibition synergistically interacts with
trastuzumab in Her-2/neu-negative
breast cancer cells engineered to overexpress Her-2/neu, thus suggesting that the molecular linkage between FAS activity and functioning of Her-2/neu cannot be explained only on the basis of a transcriptional repression of Her-2/neu gene promoter. Interestingly, while in liver and adipose tissue FAS produces fat from excess
carbon consumed as
carbohydrates, which is ultimately stored as
triglycerides, in epithelial
cancer cells, FAS activity is mainly involved in the production of
phospholipids partitioning into
detergent-resistant membrane microdomains (
lipid raft-aggregates), which point to an active role of FAS in the deregulation of membrane functioning in
tumor cells. Importantly, clusters of Her-2/neu and EGFR (erbB-1) co-localize with
lipid rafts and the
lipid environment in the cell membrane of
breast cancer cells profoundly influences their association properties and biological functions. We hypothesize that pharmacological or small interference RNA-induced inhibition of
breast cancer-associated FAS will result in major changes in the synthesis of
phospholipids which, in turn, should impair a correct cellular localization of Her-2/neu at the cellular membrane of
breast cancer cells. In this working model, FAS inhibition could induce a shift in the equilibrium between transport of Her-2/neu to and from the membrane favoring an increased Her-2/neu internalization followed by intracellular degradation, thus enhancing the mechanism of action of the anti-Her-2/neu antibody
trastuzumab. Moreover, the inhibition of FAS-driven
lipid rafts will also negatively affect EGFR-Her-2/neu cross-talk, an important mechanism of
trastuzumab resistance. In summary, the specific blockade of a novel molecular linkage between FAS-regulated membrane composition and functioning of transmembrane
growth factor receptors EGFR and Her-2/neu may represent a previously unrecognized therapeutic approach circumventing
trastuzumab resistance in
breast carcinomas.